Immune‑related pathophysiological causes relevant to a subset of patients with preeclampsia (Review)
- Hiroshi Kobayashi
- Mayuko Ichikawa
- Juria Akasaka
- Taihei Tsunemi
- Toshiyuki Sado
Affiliations: Department of Obstetrics and Gynecology, Nara Medical University, Kashihara, Nara 634‑8522, Japan
- Published online on: April 17, 2019 https://doi.org/10.3892/wasj.2019.10
Copyright: © Kobayashi
et al. This is an open access article distributed under the
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Preeclampsia is characterized by inadequate extravillous trophoblast (EVT) invasion, leading to feto‑placental hypoxia, a release of an excessof anti‑angiogenic factors, and finally eliciting maternal endothelial dysfunction and maternal symptoms, such as new‑onset hypertension and proteinuria. Despite intensive research over the past decade, the initial pathogenesis of this disorder remains elusive. There are likely different subtypes of preeclampsia and maternal, fetal and placental factors all play an important role in the disease development. In this review, we focus on an immune‑related pathway or pathophysiological causes relevant to a subset of patients with preeclampsia. Using the PubMed database, we conducted a literature review of various studies related to the pathogenesis of preeclampsia. The two‑stage theory is a notable postulate of the disease. The antecedents of poor placentation are immunological, epigenetic and environmental factors in origin. The causes of inadequate immune mechanisms at the maternal‑fetal interface in preeclampsia is considered to be a lack of human leucocyte antigen (HLA) class I molecules, such as HLA‑G and HLA‑C. A reduction in HLA molecules facilitate EVTs to elicit an immune attack that furthers cell killing. A series of the HLA‑G promoter region on EVTs has been found to be more highly methylated in preeclampsia than in normal pregnancy, possibly due to the increased expression of DNA methyltransferase‑1 (DNMT‑1). Promoter hypermethylation is one of the major epigenetic alterations that may prime for HLA‑G gene inactivation. Epigenetic alterations are reversible, and nutrition, lifestyle and environmental factors may be the epigenetic regulators that modify gene expression. However, the timing, cause and underlying mechanisms of HLA gene methylation have not yet been fully established. The adverse intrauterine environment that contributes to immune responses, inflammation, or oxidative stress may be associated with increased susceptibilities for a number of adult diseases, including preeclampsia. We have hypothesized that close interactions between the inherited epigenetic architecture (hypermethylation of HLA molecules) and adverse intrauterine environmental exposures (oxidative stress and inflammation) leading to epigenetic modifications and to the aberrant DNA methylation of HLA class I molecules, may act as an early event of preeclampsia development.